Role of endotoxemia in cardiovascular dysfunction and lethality: Virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock

We investigated whether the severity of septic shock is determined by virulence factors associated with or the levels of endotoxemia produced by two Escherichia coli strains. Canines were challenged intraperitoneally with an E. coli strain (06:H1:K-2) that has virulence factors associated with human disease or with an equal dose of a nonvirulent strain (086:H8) that lacks these factors. Both strains were administered in viable, heat-killed, and purified endotoxin forms. Median survival times with the virulent strain compared with the nonvirulent strain were shorter with viable bacteria (5 x 10(9) CFU/kg) (144 h versus >672 h; Wilcoxon, P = 0.03), longer with heat-killed bacteria (5 x 10(10) CFU/kg) (> 676 h versus 26 h; P = 0.03), and similar with purified endotoxin (15 mg/kg) (28 h versus 48 h; P = 0.71). However, whether the challenge contained viable bacteria, heat-killed bacteria, or purified endotoxin, the virulent strain produced less endotoxemia (P = 0.001). Hence, the changing outcomes with differing forms of the two strains cannot be attributed solely to endotoxin levels. The viable virulent strain caused less endotoxemia but more harm, and this does not appear to be explained by a more potent endotoxin or other heat-stable component. This study suggests that circulating endotoxin levels per se are less important in the outcome of septic shock than virulence factors associated with E. coli strains. Furthermore, the data call into question the significance of the endotoxin concentration in the blood in predicting the severity of shock and the lethality of gram-negative infections.